The present invention relates to a method of treatment for feline leukemia virus infections. Being an RNA tumor virus, which is a retrovirus, the feline leukemia virus is integrated into the DNA of its host cell. Due to infection by feline leukemia viruses, a great many types of hematopoietic diseases may develop. Specific hematopoietic diseases include, for example, immune system suppression, lymphatic leukemia, and sarcomas in lymphatic cells; agranulocytosis such as neutropenia, anemia, thrombocytopenia, and leukemia in bone marrow cells; and chronic stomatitis as complications with bacterial infection. In latter stages after infection with feline leukemia viruses, anemia and chronic stomatitis are often clinically observed, and the development of effective therapeutic agents and methods of treatment therefor has been eagerly awaited. However, although it will take many years before development of serious diseases, as described above, after infection with feline leukemia viruses, in the early stages after infection with these viruses, elevation of body temperature associated with a decrease in the number of neutrophils, decreases in vigor and appetite, and aggravation of other general clinical symptoms are often observed. Aggravation of neutropenia may sometimes result in death.
Conventionally, methods of treatment for feline leukemia virus infections mainly include symptomatic therapies using steroid hormones. Although human erythropoietin has been experimentally used as a remedy for anemia, satisfactory effects have not yet been achieved.
As causal therapies, use of synthetic anticancer agents which are human chemotherapeutics and use of a human xcex1 (alpha)-interferon have been proposed; however, the effects thereof are not satisfactory.
Hoover, et al., at Colorado State University, have attempted experimental therapies using AZT (3xe2x80x2-azido-3xe2x80x2-deoxythymidine) and a human xcex1-interferon for an immunodeficiency syndrome due to a feline leukemia virus, and have reported a reduction effect on the p27 antigen, which is an antigen of the feline leukemia virus. However, they have also admitted that the effect diminishes because antibodies are produced against the human interferon, which is a foreign protein to cats, after continued administration of the human xcex1-interferon, and thus, there is a problem in this as a method of treatment for feline leukemia virus infections. [Zeidner, N. S., Myles, M. H., Mathiason, D. C., Dreit, M. J., Mullins, J. I. and Hoover, E. A.; 1990a; Alpha Interferon(2b) in combination with zidovudine for the treatment of presymptomatic feline leukemia virus-induced immunodeficiency syndrome; Antimicrob. Agents Chemother.; 34: 1749-1749.]
Tompkins, et al., at North Carolina State University, have reported that, as treatment for feline leukemia viral lymphoma development, DEC (diethylcarbamazine) and AZT are effective at reducing p27 antigen and at prolonging life. However, neither was effective for neutropenia. [Nelson, P., Sellon, R., Novotoney, C., Devera, C., Davidian, M., English, R., Tompkins, M., and Tompkins, W.; 1995; Vet. Immunol. Immunopathol.; 46,181-194]
Cummins, et al., have orally administered to cats infected with feline leukemia viruses a low dose of a human xcex1-interferon and have reported that it is effective at prolonging life, although there is no effect on virus antigens. Although this therapy was later globally investigated as a method for treating human AIDS, the use thereof has not been implemented. [Weiss, R. C., Cummins, J. M., and Richards, A. B.; 1991; JAVMA; 199,1477-1481]
In various feline leukemia virus infections, since, in many cases, immunocompetence of cats is believed to be degraded, heavy use of steroid hormones, which are immunosuppressant agents, is not desirable, and side effects thereof often present a problem.
In addition, use of synthetic anticancer agents which are human chemotherapeutics and the oral administration of a small amount of a human xcex1-interferon are not adequately effective, and in the former synthetic anticancer agents, in particular, side effects are a problem.
As a feline interferon, a recombinant feline xcfx89-interferon preparation has already been approved as a therapeutic agent for feline calicivirus infection, and has been commercially available under the trade name xe2x80x9cINTERCATxe2x80x9d since February 1994. The present inventors have achieved the present invention as a result of the investigation of a method of treatment for feline leukemia virus infection using the recombinant feline xcfx89-interferon.
Currently interferons are known to be of the following types: alpha (xcex1), beta (xcex2), gamma (xcex3), omega (xcfx89), and tau (xcfx84). Although use of three types xcex1, xcex2, and xcex3has been implemented with respect to human interferons, in feline interferons, use of the xcfx89-type only has been implemented. xe2x80x9cINTERCATxe2x80x9d is a recombinant feline xcfx89-interferon preparation, and is an injectable preparation produced by a method including the steps of infecting a silkworm with a baculovirus having recombinant feline xcfx89-interferon genes; extracting and purifying products of the body thereof; adding thereto gelatin and D-sorbitol as stabilizers and vehicles; and freeze-drying. The recombinant feline xcfx89-interferon is a glycoprotein having a molecular weight of approximately 25,000, and the protein portion thereof has the amino acid sequence as shown in the sequence listing (SEQ ID:1).
The feline xcfx89-interferon may be produced by other methods, in addition to the use of silkworms. For example, it may be produced by a transient expression method using zooblasts such as simian COS cells, or by gene recombination techniques using CHO cells of Chinese hamsters, E. coli, yeast, transgenic animals, or the like.
With respect to the administration/dosage of INTERCAT which has been approved as a therapeutic agent for feline calcivirus infectious diseases, 2.5 to 5 MU/kg of the feline interferon is required to be administered intravenously once a day for three times every other day. Herein, an MU (megaunit) represents a titer used as a measure of the antiviral activity of the interferon, and is equal to one million units. Although treatment for feline leukemia virus infections, in particular, neutropenia, was attempted by administering INTERCAT every other day with the same administration/dosage as those for the approved therapeutic agent for feline calicivirus infections, the anticipated effects were not obtained. Therefore, by changing the administration/dosage, further investigations were carried out.
It is an object of the present invention to provide a novel and superior method of treatment which is suitable for feline leukemia virus infections, and in particular, for neutropenia.
In order to achieve the object described above, the present inventors investigated and discovered a method of treatment for feline leukemia virus infections by administering to cats by injection a therapeutic agent containing a feline xcfx89 (omega)-interferon, leading to the present invention.
That is, the object of the present invention has been achieved with industrial advantages by the present invention comprising the following aspects.
(1) A method of treatment for feline leukemia virus infections including continuous daily administration of a feline interferon preparation containing a feline interferon as a main component to a cat.
(2) A method of treatment for feline leukemia virus infections according to (1), wherein the feline interferon is a feline xcfx89 (omega)-interferon.
(3) A method of treatment for feline leukemia virus infections according to (2), wherein the feline xcfx89-interferon is a recombinant interferon.
(4) A method of treatment for feline leukemia virus infections according to (3), wherein the feline xcfx89-interferon is an interferon having an amino acid sequence shown in the sequence number 1 in which a sugar chain is connected.
(5) A method of treatment for feline leukemia virus infections according to any one of (1) to (4), wherein the injection is a subcutaneous injection.
(6) A method of treatment for feline leukemia virus infections according to any one of (1) to (5), wherein the treatment is provided for neutropenia due to infection with a feline leukemia virus.
(7) A method of treatment for feline leukemia virus infections according to any one of (1) to (6), wherein the feline xcfx89-interferon is administered in a dose of 0.5 MU/kg to 2.0 MU/kg per cat weight, at least once a day, for at least three consecutive days.
A feline interferon used in the present invention is preferably a feline xcfx89-interferon, and may be any one of a natural interferon, a chemically synthesized interferon, and an interferon produced by a genetic recombination technique.
Specifically, a feline xcfx89-interferon commercially available under the trade name xe2x80x9cINTERCATxe2x80x9d (produced by Toray Industries, Inc.) may be used, which is produced by a genetic recombination technique.
xe2x80x9cINTERCATxe2x80x9d has been approved and used as a therapeutic agent for feline calicivirus infections, and has an interferon as a main component. In the interferon, a sugar chain-is connected to-an amino acid sequence containing 170 amino acids shown in SEQ ID:1 and the interferon is obtained by infecting silkworm larvae with a recombinant baculovirus as an insect virus having recombinant feline xcfx89-interferon genes and by extracting, separating, and purifying products in the silkworm fluid.
However, a feline xcfx89-interferon in the present invention is not necessarily limited to the recombinant feline interferon described above.
In cats having feline leukemia virus infections, whose infections have been confirmed by the fact that the virus examinations of the blood of the cats reveal that feline leukemia virus antigens (FeLV antigens) are positive, in the early stage of the feline leukemia virus infection, neutropenia is particularly observed. An effective method for treating neutropenia using a therapeutic agent containing a feline xcfx89-interferon has been discovered. Neutropenia is confirmed by testing the blood of cats. In feline leukemia virus infections, in addition to a decrease in the number of neutrophils, a decrease in the number of thrombocytes is often observed.
A method of treatment discovered by the present inventors includes daily injections into a cat, at least once a day, a therapeutic agent containing a feline xcfx89-interferon. The feline interferon is administered in a dose of 0.5 MU/kg to 2.0 MU/kg per cat weight.
The number of administrations is practically once a day. Although administration may be performed more than once a day, administration at least once a day is preferable. Instead of every other day, administration every day is preferable, and daily-administration for at least three consecutive days is further preferable. If possible, daily administration for at least five consecutive days is effective. When administration must be discontinued after administering for at least three consecutive days due to the pet owner""s circumstances or the like, at an early stage after the discontinuance, another daily administration for at least three consecutive days is preferably performed.
Although a dose of less than 0.5 MU/kg may be administered, as the dose is decreased from 0.5 MU/kg, the therapeutic efficacy is decreased. On the other hand, a high dose of more than 2.0 MU/kg merely increases the treatment cost, and in many cases does not greatly increase efficacy.
With respect to the route of administration by injection, subcutaneous injections are most preferably used. Although intravenous injections are more difficult than subcutaneous injections because of difficulties in locating blood vessels, intravenous administration may be used. Although intramuscular injections are not preferable because of induced pain, in terms of efficacy, intramuscular injections may be used.
Many cats having feline leukemia virus infections are brought to veterinarians because of fever, loss of vigor, anorexia, and the like, and blood tests indicate neutropenia. In such a case, a method of treatment using a therapeutic agent containing a feline xcfx89-interferon in accordance with the present invention is preferably used. As supportive therapies, transfusions and antibiotics are also preferably administered.
Consequently, alleviation of fever, revivification, and recovery of appetite are observed, and blood tests reveal that the number of neutrophils, which had decreased, rapidly increased, and sometimes that the number of thrombocytes increased at the same time.